FDA asks uniQure for phase‑3 sham control

For a few months, uniQure looked like it might pull off something that Huntington’s disease research has never managed before. Its gene therapy, AMT-130, had produced striking late-stage follow-up data in a small Phase 1/2 program, and the company was openly planning a U.S. filing. Then the FDA said no. In final minutes from a January 30, 2026 Type A meeting, the agency told uniQure that the existing studies, measured against an external natural-history control, do not provide the primary evidence of effectiveness needed for approval. The FDA “strongly recommended” a prospective, randomized, double-blind, sham surgery-controlled trial instead (sec.gov, fiercebiotech.com). That is a brutal reset because AMT-130 is not a pill that can be tested with a simple placebo. It is a one-time gene therapy delivered directly into the striatum through neurosurgery. The treatment uses an AAV5 vector to carry an artificial microRNA designed to silence the huntingtin gene and lower production of the toxic protein that drives the disease (uniqure.com, clinicaltrials.gov). A sham-controlled trial means some patients would go through the theater and risk of brain surgery without getting the active therapy. That is exactly why uniQure had tried to build its case around treated patients versus matched patients from Enroll-HD, a large natural-history database, instead of running a conventional Phase 3 study (clinicaltrials.gov, eurohuntington.org). The company did not choose that shortcut because the data were weak. It chose it because the data looked unusually strong for Huntington’s disease. In September 2025, uniQure said the high-dose cohort met the study’s prespecified primary endpoint, with a statistically significant 75% slowing of disease progression on cUHDRS at 36 months compared with a propensity score-matched external control. It also said the therapy hit a key secondary endpoint on Total Functional Capacity, while cerebrospinal fluid neurofilament light levels sat below baseline at 36 months (hdsa.org, cgtlive.com). Those results built on a July 2024 interim update that had already suggested dose-dependent slowing of decline over 24 months (hdsa.org). The surprise is not that the FDA wanted rigor. The surprise is that the agency had previously signaled a much more flexible path. AMT-130 had already collected Fast Track, Orphan Drug, RMAT, and then Breakthrough Therapy designation in April 2025, with that last label explicitly tied to clinical evidence that the therapy might substantially improve outcomes in a disease with no approved disease-modifying treatment (uniqure.com, huntington-disease.org). By late 2025, uniQure was talking about a biologics license application. By March 2, 2026, it was talking about Phase 3 design discussions in a future Type B meeting instead (huntington-disease.org, sec.gov). That reversal turned a scientific story into a regulatory one. The FDA is effectively saying that for an irreversible brain gene therapy, promising signals and clever external controls are not enough. It wants the old standard, even if the old standard means sham brain surgery in a rare, fatal disease. uniQure’s own trial registry already shows why this is so hard: the U.S. Phase 1/2 study enrolled just 43 patients and is not expected to fully wrap up until late 2029 (clinicaltrials.gov). Now the company has to figure out how to build an even larger study around a procedure that starts with drilling into the skull.